Abstract: General anesthesia is a drug-induced, reversible condition comprised of five behavioral states: loss of consciousness, amnesia, analgesia, lack of movement, and hemodynamic stability. Over 100,000 patients annually receive general anesthesia in the United States for surgical and medical procedures, yet the mechanisms for general anesthesia remain a mystery of modern medicine. While considerable safety improvements in anesthetic drugs and monitoring have been made over the past several decades, anesthesiarelated morbidity remains a significant medical problem. Approximately 1 in 500 patients experience post-operative recall of events during surgery, which can result in posttraumatic stress disorder. Up to 41% of elderly patients suffer from post-operative cognitive dysfunction, with long-term deficits found in 13% of such patients. The human and economic costs of post-operative cognitive dysfunction will continue to grow significantly as the population of the United States ages and requires more frequent surgical and medical intervention. Other frequent side effects of general anesthesia include cardiovascular and respiratory depression, nausea, and vomiting. These instances of anesthesia-related morbidity occur because anesthetic drugs affect the entire central nervous system, not just the specific brain areas required to produce the state of general anesthesia. Because we are unable to monitor brain activity intraoperatively within the desired target brain systems, it is a challenge at present to balance the desired anesthetic state against unintended side effects. Furthermore, we lack the means to deliver anesthetic drugs specifically to anesthesia-related brain systems in order to avoid side effects mediated in other brain systems. We present here an innovative research program that will develop neural systems-based anesthetic monitoring and drug delivery to eliminate anesthesia-related morbidity. The proposed studies will result not only in dramatically improved anesthesia care in the long term, but will also result in fundamental discoveries and developments in systems neuroscience, neuroimaging, and drug delivery. Public Health Relevance: This innovative research program will develop neural systems-based monitoring and drug delivery for general anesthesia. These studies have the potential to dramatically improve healthcare for over 28 million patients who receive general anesthesia annually in the United States by reducing or eliminating the incidence of post-operative recall, post-operative cognitive dysfunction, and potentially life-threatening intraoperative cardiovascular and respiratory depression. The proposed studies will result not only in dramatically improved anesthesia care in the long term, but will also result in fundamental discoveries and developments in systems neuroscience, neuroimaging, and drug delivery.